Neuroscience Forefront ReviewAlcohol, stress hormones, and the prefrontal cortex: A proposed pathway to the dark side of addiction
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Section snippets
Overview
Alcoholism is a neurobehavioral disorder characterized by compulsive seeking of alcohol, excessive and uncontrolled intake, and the emergence of a negative emotional state (e.g., irritability, anxiety, depression) when alcohol is unavailable (American Psychiatric Association, 1994). Preclinical studies in rodents suggest that the transition from alcohol use to abuse to dependence is due to alterations in stress-related neural pathways resulting from exposure to repeated cycles of alcohol
Alcohol use disorders and prefrontal cortex
The prefrontal cortex integrates information from other cortical and subcortical regions to functionally contribute to working memory, emotion regulation, and behavioral control (Wilson et al., 2010, Kesner and Churchwell, 2011). Structural, physiological, and behavioral deficits related to the prefrontal cortex have been observed in alcohol use disorder patients. These functional changes include reduced glucose metabolic rates, cortical atrophy, decreased cognitive flexibility, and memory
Animal models of alcohol use, abuse, and dependence
Preclinical rodent models aim to emulate as much as possible the human experience with alcohol by capturing different drinking behaviors in the early, mid, and late stages of addiction (Brown et al., 1980). Fig. 1 provides an overview of commonly used rodent models of alcohol use, abuse and dependence. For more detailed discussion of the preclinical nonhuman primate models see (Grant and Bennett, 2003, Barr and Goldman, 2006). When people consume alcohol, most of them drink low-to-moderate
Alcohol stimulates the release of stress hormones
When an organism experiences a physical or psychological challenge, neurons in the paraventricular nucleus of the hypothalamus (PVN) release the 41-amino acid peptide corticotrophin-releasing factor (also known as corticotropin-releasing hormone) from axonal terminals in the median eminence (Vale et al., 1981). Corticotropin-releasing factor (CRF) travels through the short portal system, binds to its Type 1 G-protein-coupled receptor (CRF1) (Chang et al., 1993, Chen et al., 1993, Perrin et al.,
Chronic exposure to alcohol leads to neuroendocrine tolerance
Chronic heavy alcohol use eventually leads to dampened functioning of the neuroendocrine stress system and this dysregulated hormonal state may contribute to some of the symptoms of alcoholism (Lovallo, 2006, Li et al., 2011, Sinha et al., 2011, Stephens and Wand, 2012). Animal studies have elucidated some of the functional changes in the HPA axis that emerge after varying degrees of prolonged alcohol exposure in drinking models of addiction. Early in abstinence after chronic alcohol exposure,
Neuroendocrine tolerance may trigger relapse and heavy drinking
As described above, HPA dysregulation is a common symptom associated with chronic alcohol abuse and dependence. Reduced stress hormone levels may not only be reliable indicators of the addictive stage of an individual, but could also play a functional role in driving escalated drinking and enhanced relapse. In support of this hypothesis, blunted basal stress hormone levels in alcoholics predict craving (Kiefer et al., 2002). There is also a strong temporal relationship between dampened HPA
Role of glucocorticoids in the transition to dependence
Even with chronic alcohol dampening the neuroendocrine stress system, glucocorticoids still play a powerful role in the transition to dependence. Chronic exposure to alcohol drinking or to vapor-induced bouts of intoxication leads to dampen peripheral glucocorticoid levels (Richardson et al., 2008, Silva et al., 2009), yet glucocorticoid signaling is required for the development of the physical, motivational, and cognitive syndromes associated with alcohol dependence in rodents (Sze, 1977,
Glucocorticoids may target the medial prefrontal cortex (mPFC) to produce some of the neuroendocrine and behavioral changes associated with dependence
Glucocorticoids initiate non-genomic and genomic cellular events that provide both immediate and long-term effects, respectively (Kolber et al., 2008). The fluctuating levels of glucocorticoids during alcohol intoxication and after abstinence, as described above, could induce assorted adaptation processes in the brain. Although there are most likely several targets undergoing GR-mediated neuroadaptive changes following chronic alcohol, here we focus on the prefrontal cortex—a region of the
Conclusions
We propose that acute stimulation of the HPA axis during repeated bouts of intoxication and the subsequent adaptation within this neuroendocrine axis and upstream in the prefrontal cortex are key factors in the transition from alcohol use to abuse and eventually to dependence. As individuals engage in repeated cycles of intoxication, abstinence, and relapse, a dynamic cascade of glucocorticoid signaling could trigger a series of neuroadaptive events in the prefrontal cortex that have broad
Acknowledgements
We thank Jesse McClure for his critical reading of the manuscript. Our work is supported by the National Institutes of Health and the National Institute on Alcohol Abuse and Alcoholism: AA021013 (HNR).
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